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Part 1. Overview Information

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Background

The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of promising complementary and integrative health approaches with physical and/or psychological therapeutic inputs (often called mind and body interventions). These mind and body interventions are widely used by the public, and they are increasingly recognized as a nonpharmacologic approach to symptom management (e.g., chronic pain, mild depression, anxiety). These approaches can be used by individuals to help prevent, treat, or self-manage various conditions, and they can be complementary to conventional health care.

There is a need for research to evaluate mind and body approaches as they are used and delivered to determine whether they are safe and efficacious or effective for given conditions or disorders. For clinical trials to address this need, they must be well designed and test hypotheses that will guide decisions about the inclusion of these interventions or approaches in health care for a given condition or disorder. Investigators need to cite published literature or conduct a series of early-phase clinical trials to gather the multiple types of information to design subsequent large and rigorous efficacy or effectiveness studies. Although the scientific literature may provide the rationale for conducting an efficacy or effectiveness trial, investigators may lack critical information about key elements needed to plan and conduct such a trial. Some key aspects that may need further investigation to plan the future clinical trial could include refining or adapting the intervention to specific populations, modalities, or settings; assessing the feasibility, acceptability, and adherence to protocolized multi-component interventions; and/or finalizing the intervention delivery method, appropriate outcome(s), or recruitment strategy. Feasibility clinical trials can fill these information gaps.

Overview of NCCIH Mind and Body Clinical Trials Research Funding Opportunities

NCCIH has designed a framework for research to describe the broad spectrum of complementary and integrative health research it supports (https://www.nccih.nih.gov/grants/nccih-research-framework). NCCIH supports investigators working on the continuum of the research framework, from basic science, and feasibility research, through high-impact clinical trials as well as research on dissemination and implementation (https://www.nccih.nih.gov/grants/funding/clinicaltrials). We encourage investigators to examine the full suite of available clinical trial notices of funding opportunities (NOFOs) to determine which one best aligns with the proposed stage of intervention development and testing.

NCCIH has an oversight process to provide stewardship and maintain excellence, integrity, and rigor in our supported clinical studies (https://www.nccih.nih.gov/grants/toolbox). Investigators are encouraged to review the NCCIH Clinical Terms of Award for Human Subjects Research (https://www.nccih.nih.gov/research/nccih-clinical-terms-of-award-for-human-subjects-research) to learn more about NCCIH’s requirements for clinical research.

Prior to submitting a grant application, NCCIH strongly encourages consulting with NCCIH Scientific/Research extramural program contacts relevant to the area of science for which they are planning to develop an application. Early contact provides an opportunity for NCCIH staff to discuss the scope and goals, and to provide information and guidance.

Research Objectives of the Mind and Body Feasibility Clinical Trial Phase (R34)

The objective of this NOFO is to support the development of building blocks to plan and conduct novel, high priority clinical trials of complementary and integrative health approaches with physical and/or psychological therapeutic inputs (often called mind and body interventions) to enhance the probability of reaching more definitive outcomes in a future clinical trial. Important building blocks that could be supported under this NOFO include refining the experimental protocols, including the assessment protocol, experimental intervention protocol, comparison intervention protocol, and randomization procedures; examining the feasibility of recruiting and retaining participants in the study; and developing supportive materials and resources. Investigators should design the R34 to provide the necessary preliminary data to fill gaps in the literature to justify a future efficacy, effectiveness, pragmatic, or dissemination and implementation trial. Applications should describe and justify the need for feasibility data and ensure that no other published or completed pilot studies have been performed with a similar population and similar intervention. If it is possible to reference successful demonstration of these benchmarks in completed trials or trials currently underway using the proposed or similar intervention and study population, further single-site feasibility work is not needed. Applications proposing such iterative or duplicative studies will be considered of low programmatic relevance, which will decrease likelihood of funding.

The following are examples of the types of aims appropriate for feasibility clinical trials proposed under this NOFO:

  • Assessment of acceptability and adherence to dose, frequency, and/or duration of the intervention.
  • Substantial intervention refinement to tailor, adapt, or customize an intervention to a new population, modality, or setting. The need for adaptation/tailoring should be based upon a strong scientific rationale for the proposed adaptation. Comparisons on feasibility outcomes between the adapted intervention to the original intervention are strongly encouraged.
  • Development and assessment of acceptability or adherence to a protocolized multi-component intervention.
  • Iterative intervention refinement via several small cohorts to address challenges with intervention fidelity, participant adherence, or selection of appropriate outcomes.
  • Assessment of feasibility to measure outcomes within designated time frames; train interventionists to deliver the intervention with fidelity; and/or recruit, randomize, and retain participants in the intervention or comparison condition.
  • Development and feasibility testing of the strategies for integrating a mind and body approach into a health care system or delivery, to inform design of future pragmatic or implementation science trials.
  • Assessment of acceptability or feasibility of randomization or other aspects of trial design.
  • Development and feasibility testing of an appropriate control/comparison intervention for a future larger study.
  • Demonstration of feasibility of an intervention to be delivered remotely (e.g., tailoring of an algorithm for use in an mHealth intervention or smartphone application).

Design Considerations

Investigators should propose a randomized controlled trial design with at least one intervention arm and one comparator arm. There should be strong rationale for the comparator condition (e.g., time and attention control, usual care, standard of care, sham condition, and/or active comparator(s)) based on the research question you plan to address in the future powered trial. Due to lack of rigor and potential expectancy effects, NCCIH will not support studies proposing a waitlist comparator condition.

Power Recommendations:

Pilot or feasibility studies are carried out in preparation for future large-scale, adequately powered studies and, therefore, should address key feasibility issues such as participant recruitment and retention; burden and adherence to the intervention; provider fidelity to the intervention; and data collection methods. Given the limited sample sizes that can be supported under this R34 grant mechanism, proposing to conduct fully powered tests of clinical outcomes (i.e., efficacy) or underpowered tests of outcomes (i.e., “preliminary efficacy”) or attempting to utilize the highly variable point estimate of an effect size for power calculations would be non-responsive as noted below. As pilot and feasibility studies are not designed (or powered) to address efficacy or effectiveness of an approach or intervention, statistical methods should be mainly descriptive. Applicants should define feasibility/acceptability with quantitative benchmarks corresponding to each assessment category. Scientific and/or statistical justification should be provided to demonstrate how the sample size is sufficient to make a feasibility/acceptability determination in accordance with benchmarks. Sample sizes used in pilot studies are not powered for testing pre-specified hypotheses as expected for confirmatory studies. Sample sizes for subsequent fully powered studies should be based on determining a clinically meaningful improvement due to the intervention in the appropriate research population. Investigators should consult the NCCIH website (https://www.nccih.nih.gov/grants/pilot-studies-common-uses-and-misuses) for more information on the uses and misuses of feasibility studies.

Group-Based Interventions:

In some cases, investigators who wish to evaluate the effect of an intervention on a health-related biomedical or behavioral outcome may propose a study in which (1) groups or clusters are assigned to study arms and individual observations are analyzed to evaluate the effect of the intervention, or (2) participants are assigned individually to study arms but receive at least some of their intervention in a real or virtual group or through a shared facilitator. Investigators should provide a strong rationale for the choice among trial design options. The selection of study design should be guided by decisions about how best to deliver the intervention and by concerns regarding contamination and logistics. Applicants should show that their methods are appropriate given their plans for assignment of participants and delivery of interventions. Additional information is available at https://researchmethodsresources.nih.gov/.

Mechanistic Measures:

There are often questions about whether feasibility trials should include mechanistic aims to evaluate how interventions work. Trials submitted under this NOFO should not include aims to assess the impact/efficacy of an intervention on a mechanism of action or evaluate mediation effects. Mechanistic measures may be included in feasibility trials for the purpose of determining if collecting the mechanistic measure is feasible, which can inform whether mediation or moderation aims should be included in a future, large-scale efficacy or effectiveness trial. Applications would need to justify why the mechanistic outcome(s) should be included in the future efficacy or effectiveness trial. The inclusion of mechanistic measures should not introduce significant burden for participants or utilize a significant portion of the budget. NCCIH has other funding mechanisms to support basic, mechanistic and translational research (NOT-AT-21-006).

Preliminary Data Requirements

Preliminary data are not required for this NOFO unless the application involves a natural product (i.e. botanicals, probiotics, and products marketed as dietary supplements) as part of a multi-component intervention. However, there should be a clear and compelling scientific rationale for the need for a feasibility study or intervention adaptation.

For applications studying the feasibility or acceptability of including a natural product as part of a multi-component intervention, the application must provide published data that the formulation of the proposed natural product has demonstrated efficacy for the condition being studied from at least one fully powered placebo-controlled trial. Trials including natural products will have to adhere to the NCCIH Policy on Natural Product Integrity (http://NCCIH.nih.gov/research/policies/naturalproduct.htm).

Timeline

Investigators should propose a realistic timeline for the startup and completion of the clinical trial and provide contingency plans to proactively confront potential delays or disturbances to the planned trial.

NCCIH Priorities for Clinical Trials of Mind and Body Interventions

NCCIH has identified targeted areas of investigation to align with the NCCIH Strategic Plan (https://www.nccih.nih.gov/about/strategic-plans-and-reports). For this funding opportunity, applications will be considered high programmatic priority if they address one of following criteria related to the intervention of study:

  • The complementary or integrative approaches with physical and/or psychological therapeutic inputs (often called mind and body interventions) should include one or more of the following:
    • Physical approaches such as spinal manipulation or mobilization, massage, tai chi, qi gong, yoga, acupuncture; or
    • Psychological approaches such as hypnosis, guided imagery, breathing exercises, progressive relaxation, meditation, biofeedback, mindfulness techniques, music or other art-based therapies
    • Multi-component interventions such as naturopathic medicine, traditional Chinese medicine, Ayurvedic medicine, chiropractic care, or a combination of two or more of the specific complementary health approaches (e.g., massage and biofeedback, or natural product and mindfulness); or integrated approaches to care in which a complementary health approach is used in combination with standard care (e.g., mindfulness or yoga as augmentation to conventional medications); or
    • Multilevel intervention level (patient, caregivers of patient, clinicians, and health care system) where at least one level of intervention includes a mind and body intervention.
  • In addition, proposed projects could include an outcome measure(s) that relates to at least one of the following high-priority topic areas:
    • Promotion of health behaviors, health restoration, emotional well-being, or resilience;
    • Prevention or treatment of symptoms such as sleep disorders or disturbances, depression, anxiety, chronic stress, post-traumatic stress (disorder), obesity, and acute and chronic pain conditions;
    • Whole person health outcomes including multisystem or multilevel outcomes;
    • Minority health and reduction of disparities in areas such as pain, obesity, mental and emotional behavioral health, and maternal health;
    • Social and structural determinants of health (https://www.ninr.nih.gov/researchandfunding/nih-sdohrcc);
    • Enhancement of adherence to medications or prescribed behavioral approaches (e.g., physical activity and healthy eating);
    • Reduction or deprescribing of inappropriate use of medications or other substances (e.g., drugs of abuse or medications that are contraindicated in specific patient populations); or
    • Reduction in risk for/incidence of HIV, or comorbidities, coinfections and complications from HIV (https://abs2.od.nih.gov/Docs/NIH_StrategicPlan_FY2021-2025.pdf)

When evidence justifies, NCCIH encourages applications to conduct studies in a way that assesses the impact of integrating interventions into relevant settings (e.g., health care systems, schools, Federally Qualified Health Centers, military or Veteran health care delivery organizations, community organizations, justice systems, or homeless shelters).

All National Institutes of Health (NIH)-funded research must adhere to the Code of Federal Regulations, which outlines specific requirements to enhance protections for pregnant women, human fetuses, and neonates; children; and prisoners (https://grants.nih.gov/policy/humansubjects/policies-and-regulations/vulnerable-populations.htm). The Inclusion Across the Lifespan policy requires that individuals of all ages, including children (i.e. individuals under the age of 18) and older adults, must be included in all human subjects research, conducted or supported by NIH, unless there are scientific or ethical reasons not to include them (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-116.html).

Applications proposing research topics not identified above as high programmatic priority can be submitted but may be considered lower programmatic priority, which may reduce the likelihood of funding. Applications proposing research studies using an intervention and patient population that are the same as or very similar to those used in studies already in progress, conducted, or published by other groups are likely to be lower programmatic priority.

Clinical Trials Not Responsive to this NOFO

The following types of clinical trials are not responsive to this NOFO, and applications proposing such activities will be deemed non-responsive and not reviewed:

  • Studies proposing to analyze data from a feasibility trial to assess efficacy/effectiveness of an intervention or estimate effect size (https://www.nccih.nih.gov/grants/pilot-studies-common-uses-and-misuses).
  • Trials that do not include an aim to assess the feasibility, acceptability, fidelity, and/or adherence to the intervention.
  • Studies that do not include a mind and body intervention.
  • Studies that propose a waitlist control.
  • Trials that propose to assess feasibility of interventions for the treatment or prevention of cancer. (Investigators interested in cancer treatment or prevention trials should contact the National Cancer Institute.)